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Abstract: Objective: The purpose of this study was to investigate the tissue distribution of lidocaine hydrochloride in mandibular bone marrow after intraosseous anesthesia (IOA) in rabbits. Methods: We used macroautoradiography to examine the tissue distribution of a 14C-labeled 2% lidocaine hydrochloride solution containing 1:80,000 epinephrine (14C-lidocaine). Under general anesthesia, 14C-lidocaine was injected intraosseously or paraperiosteally. After IOA, animals were divided into three groups and observed at 1 (IOA-1), 5 (IOA-5), and 10 minutes (IOA-10) after injection. After infiltration anesthesia (IA), animals were observed at 1 minute after injection. Results: The accumulation of 14C-lidocaine was observed around the injection site in both the IA and the IOA groups. Paraperiosteally injected 14C-lidocaine diffused to the surrounding tissues such as the lip, whereas IOA showed concentrated accumulation around the root apex throughout the experiment. The distribution area was significantly smaller in the IOA-1 group than in the IA group. The distribution area in the IOA-5 group was larger than those in the IOA-1 and IOA-10 groups. Conclusions: The accumulation of 14C-lidocaine injected by IOA in rabbits was concentrated around the root apex. These results may explain the rapid onset time of IOA. [Copyright &y& Elsevier]

In this study, by measuring bispectral index (BIS), we tested the hypothesis that intravenous adenosine 5'-triphosphate (ATP) infusion would deepen the level of midazolam-induced sedation. Ten healthy volunteers underwent 2 experiments with at least 2 weeks' interval: immediately after intravenous bolus administration of midazolam (0.04 mg/kg), they received continuous infusion of either ATP infusion (100 μg/kg/min) or placebo (saline) for 40 minutes in a double-blind, randomized, crossover manner. Changes in BIS values and responsiveness to verbal command as well as cardiorespiratory variables were observed throughout the study periods. Administration of midazolam alone reduced BIS value from control: 97 ± 1 to 68 ± 18 at 25 minutes, which was accompanied by significant cardiopulmonary depressant effects, while maintaining responsiveness to verbal command (consciousness) throughout the study period. Coadministration of ATP with midazolam further reduced BIS value to 51 ± 13, associated with complete loss of consciousness without adverse effect on the cardiorespiratory systems. We conclude that the addition of ATP infusion to midazolam significantly enhances midazolam sedation without disturbing cardiorespiratory functions. [ABSTRACT FROM AUTHOR]

The ionotropic P2X receptor, P2X7, is believed to regulate and/or generate nociceptive pain, and pain in several neuropathological diseases. Although there is a known relationship between P2X7 receptor activity and pain sensing, its detailed functional properties in trigeminal ganglion (TG) neurons remains unclear. We examined the electrophysiological and pharmacological characteristics of the P2X7 receptor and its functional coupling with other P2X receptors and pannexin-1 (PANX1) channels in primary cultured rat TG neurons, using whole-cell patch-clamp recordings. Application of ATP and Bz-ATP induced long-lasting biphasic inward currents that were more sensitive to extracellular Bz-ATP than ATP, indicating that the current was carried by P2X7 receptors. While the biphasic current densities of the first and second components were increased by Bz-ATP in a concentration dependent manner; current duration was only affected in the second component. These currents were significantly inhibited by P2X7 receptor antagonists, while only the second component was inhibited by P2X1, 3, and 4 receptor antagonists, PANX1 channel inhibitors, and extracellular ATPase. Taken together, our data suggests that autocrine or paracrine signaling via the P2X7-PANX1-P2X receptor/channel complex may play important roles in several pain sensing pathways via long-lasting neuronal activity driven by extracellular high-concentration ATP following tissue damage in the orofacial area. [ABSTRACT FROM AUTHOR]

This is a case report of an infant who underwent thyrolingual cystectomy under general anesthesia. Two tracheal tubes were used: 1 for nasopharyngeal airway and the other for fiberoptic intubation. With this method, nasal intubation was successfully performed without hypoxia and hypercapnia even in a 3-month-old infant. We concluded this is a useful intubation method for infants who are predicted to be a difficult intubation. [ABSTRACT FROM AUTHOR]

Opioids are almost mandatorily used for analgesia for cancer pain and postoperative pain. Opioid analgesics commonly induce nausea as a side effect. However, the genetic factors involved are still mostly unknown. To clarify the genetic background of individual differences in the occurrence of nausea during opioid administration, the incidence of nausea was investigated in 331 patients (Higashi-Sapporo Hospital [HS] group) who received morphine chronically for cancer pain treatment and in 2021 patients (Cancer Institute Hospital [CIH] group) who underwent elective surgery under general anesthesia. We conducted a genome-wide association study of nausea in HS samples. Among the top 20 candidate single-nucleotide polymorphisms (SNPs), we focused on the TMEM132C rs7296262 SNP, which has been reportedly associated with psychiatric disorders. The rs7296262 SNP was significantly associated with nausea in both the HS and CIH groups (TT+TC vs. CC; HS group, p = 0.0001; CIH group, p = 0.0064). The distribution of nausea-prone genotypes for the rs7296262 SNP was reversed between HS and CIH groups. These results suggest that the TMEM132C rs7296262 SNP is significantly associated with nausea during opioid use, and the effect of the SNP genotype on nausea is reversed between chronic and acute phases of opioid use. [ABSTRACT FROM AUTHOR]

Patients with chronic pain are affected psychologically and socially. There are also individual differences in treatment efficacy. Insufficient research has been conducted on genetic polymorphisms that are related to individual differences in the susceptibility to chronic pain. Autoimmune disorders can lead to inflammation and chronic pain; therefore, we focused on the autoimmune-related protease-activated receptor 2 (PAR2/F2RL1) and interleukin 17A (IL-17A/IL17A) genes. PAR2 and IL-17A are associated with autoimmune diseases that lead to chronic pain, and PAR2 regulates T-helper (Th) cell activation and differentiation. We hypothesized that the PAR2 and IL-17A genes are associated with chronic pain. The present study used a case–control design to statistically examine associations between genetic polymorphisms and the vulnerability to chronic pain. The rs2243057 polymorphism of the PAR2 gene and rs3819025 polymorphism of the IL-17A gene were previously reported to be associated with pain- or autoimmune-related phenotypes. Thus, these polymorphisms were investigated in the present study. We found that both rs2243057 and rs3819025 were significantly associated with a susceptibility to chronic pain. The present findings revealed autoimmune-related genetic factors that are involved in individual differences in chronic pain, further aiding understanding of the pathomechanism that underlies chronic pain and possibly contributing to future personalized medicine. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate whether fibroblast growth factor 4 (FGF4) and FGF9 are active in dentin differentiation. Dentin matrix protein 1 (Dmp1) -2A-Cre transgenic mice, which express the Cre-recombinase in Dmp1-expressing cells, were crossed with CAG-tdTomato mice as reporter mouse. The cell proliferation and tdTomato expressions were observed. The mesenchymal cell separated from neonatal molar tooth germ were cultured with or without FGF4, FGF9, and with or without their inhibitors ferulic acid and infigratinib (BGJ398) for 21 days. Their phenotypes were evaluated by cell count, flow cytometry, and real-time PCR. Immunohistochemistry for FGFR1, 2, and 3 expression and the expression of DMP1 were performed. FGF4 treatment of mesenchymal cells obtained promoted the expression of all odontoblast markers. FGF9 failed to enhance dentin sialophosphoprotein (Dspp) expression levels. Runt-related transcription factor 2 (Runx2) was upregulated until day 14 but was downregulated on day 21. Compared to Dmp1-negative cells, Dmp1-positive cells expressed higher levels of all odontoblast markers, except for Runx2. Simultaneous treatment with FGF4 and FGF9 had a synergistic effect on odontoblast differentiation, suggesting that they may play a role in odontoblast maturation. [ABSTRACT FROM AUTHOR]

Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. The present study focused on the CACNA1C gene, which encodes the α1C subunit of the Cav1.2 L-type Ca2+ channel (LTCC) that has been reported to be associated with neuropathic pain in previous studies. We investigated genetic polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 33 patients with PTP and 118 patients without PTP but with pain or dysesthesia in the orofacial region. From within and around the CACNA1C gene, 155 polymorphisms were selected and analyzed for associations with clinical data. We found that the rs216009 single-nucleotide polymorphism (SNP) of the CACNA1C gene in the recessive model was significantly associated with the vulnerability to PTP. Homozygote carriers of the minor C allele of rs216009 had a higher rate of PTP. Nociceptive transmission in neuropathic pain has been reported to involve Ca2+ influx from LTCCs, and the rs216009 polymorphism may be involved in CACNA1C expression, which regulates intracellular Ca2+ levels, leading to the vulnerability to PTP. Furthermore, psychological factors may lead to the development of PTP by modulating the descending pain inhibitory system. Altogether, homozygous C-allele carriers of the rs216009 SNP were more likely to be vulnerable to PTP, possibly through the regulation of intracellular Ca2+ levels and affective pain systems, such as those that mediate fear memory recall. [ABSTRACT FROM AUTHOR]

Autotaxin, encoded by the ENPP2 gene, is a known key element of neuropathic pain; however, its involvement in nociceptive pain processing remains unclear. We explored the associations between postoperative pain intensity, 24-h postoperative opioid dose requirements, and 93 ENNP2-gene single-nucleotide polymorphisms (SNPs) in 362 healthy patients who underwent cosmetic surgery using the dominant, recessive, and genotypic models. Next, we validated the associations between relevant SNPs on the one hand and pain intensity and daily opioid dosages on the other in 89 patients with cancer-related pain. In this validation study, a Bonferroni correction for multiplicity was applied on all relevant SNPs of the ENPP2 gene and their respective models. In the exploratory study, three models of two SNPs (rs7832704 and rs2249015) were significantly associated with postoperative opioid doses, although the postoperative pain intensity was comparable. In the validation study, the three models of the two SNPs were also significantly associated with cancer pain intensity (p < 0.017). Patients with a minor allele homozygosity complained of more severe pain compared with patients with other genotypes when using comparable daily opioid doses. Our findings might suggest that autotaxin is associated with nociceptive pain processing and the regulation of opioid requirements. [ABSTRACT FROM AUTHOR]

Purpose: Although there have been many reports on the effects of midazolam on vital function and the recovery profile, little is known about muscle power during sedation. The purpose of this study was to investigate the effects of midazolam on muscle power during moderate sedation. Materials and Methods: The subjects were 20 male volunteers classified as American Society of Anesthesiologists physical status I. Each subject underwent 2 experiments in a randomized crossover manner (midazolam and control groups). After baseline data were obtained, midazolam (0.05 mg/kg) was administered. Thirty minutes after midazolam administration, flumazenil (0.5 mg) was administered to antagonize the sedative effects of midazolam in the midazolam group. Heart rate, noninvasive blood pressure, arterial oxygen saturation, respiratory rate, and the bispectral index value were monitored. The Observer''s Assessment of Alertness/Sedation scale and the correct-answer rate of the Stroop color word test were assessed. To evaluate muscle power, grip strength and bite force were measured. After baseline measurement, all variables were measured 2, 5, 10, 20, and 30 minutes after midazolam administration and 5, 10, and 20 minutes after flumazenil administration. For statistical comparisons, repeated measures analysis of variance, the Friedman χ2 test, and the Student t test for paired samples were used. Results: No significant changes were observed for any variable in the control group. In the midazolam group, the bispectral index value and the Observer''s Assessment of Alertness/Sedation scale decreased during midazolam sedation. The correct-answer rate of the Stroop color word test decreased 5 and 10 minutes after midazolam administration. Grip strength decreased during midazolam sedation. Bite force increased immediately after midazolam administration and remained increased even after flumazenil administration. Conclusions: Although the detailed mechanisms are unknown, bite force increases despite the muscle-relaxant action of midazolam during sedation and persists even with flumazenil reversal. [Copyright &y& Elsevier]

Objective: To compare the effects of 10% dextran and epinephrine on intraosseous injection with lidocaine in rabbits. Study design: Twenty male Japanese white rabbits were used. The effect of intraosseous injection was evaluated using an electromyogram (EMG) of the digastric muscle after electrical pulp stimulation. Two percent lidocaine alone (L), 2% lidocaine containing 1:80000 epinephrine (LE8), 2% lidocaine containing 1:160 000 epinephrine (LE16), and 2% lidocaine containing 10% dextran (LD) were tested. Electromyogram recordings were repeated before and 30 seconds, 1, 2, 3, 4, 5, 7, 10, 12, 15, and 20 minutes after the intraosseous injection. Thereafter, recordings were repeated every 5 minutes until the EMG recovered to the control value. Results: There was no difference in the onset time between the 4 groups. The order of the duration of maximum effect was LE8 >LE16 = LD ≥L. The order of the duration of anesthesia was LE8 >LE16 = LD >L. Conclusion: Ten percent dextran potentiates local anesthetic effects of 2% lidocaine in intraosseous injection. The potency of 10% dextran is comparable to 1:160 000 epinephrine. [Copyright &y& Elsevier]

Chronic pain is reportedly associated with the transient receptor potential canonical 3 (TRPC3) gene. The present study examined the genetic associations between the single-nucleotide polymorphisms (SNPs) of the TRPC3 gene and chronic pain. The genomic samples from 194 patients underwent linkage disequilibrium (LD) analyses of 29 SNPs within and around the vicinity of the TRPC3 gene. We examined the associations between the SNPs and the susceptibility to chronic pain by comparing the genotype distribution of 194 patients with 282 control subjects. All SNP genotype data were extracted from our previous whole-genome genotyping results. Twenty-nine SNPs were extracted, and a total of four LD blocks with 15 tag SNPs were observed within and around the TRPC3 gene. We further analyzed the associations between these tag SNPs and chronic pain. The rs11726196 SNP genotype distribution of patients was significantly different from the control subjects even after multiple-testing correction with the number of SNPs. The TT + TG genotype of rs11726196 is often carried by chronic pain patients, suggesting a causal role for the T allele. These results contribute to our understanding of the genetic risk factors for chronic pain. [ABSTRACT FROM AUTHOR]

An inflammatory response following dental pulp injury and/or infection often leads to neurogenic inflammation via the axon reflex. However, the detailed mechanism underlying the occurrence of the axon reflex in the dental pulp remains unclear. We sought to examine the intracellular cyclic adenosine monophosphate (cAMP) signaling pathway in odontoblasts via the activation of Gs protein-coupled receptors and intercellular trigeminal ganglion (TG) neuron–odontoblast communication following direct mechanical stimulation of TG neurons. Odontoblasts express heterotrimeric G-protein α-subunit Gαs and calcitonin receptor-like receptors. The application of an adenylyl cyclase (AC) activator and a calcitonin gene-related peptide (CGRP) receptor agonist increased the intracellular cAMP levels ([cAMP]i) in odontoblasts, which were significantly inhibited by the selective CGRP receptor antagonist and AC inhibitor. Mechanical stimulation of the small-sized CGRP-positive but neurofilament heavy chain-negative TG neurons increased [cAMP]i in odontoblasts localized near the stimulated neuron. This increase was inhibited by the CGRP receptor antagonist. In the mineralization assay, CGRP impaired the mineralization ability of the odontoblasts, which was reversed by treatment with a CGRP receptor antagonist and AC inhibitor. CGRP establishes an axon reflex in the dental pulp via intercellular communication between TG neurons and odontoblasts. Overall, CGRP and cAMP signaling negatively regulate dentinogenesis as defensive mechanisms. [ABSTRACT FROM AUTHOR]

Considerable individual differences are widely observed in the sensitivity to opioid analgesics. We focused on rs12496846, rs698705, and rs10052295 single-nucleotide polymorphisms (SNPs) in the C3orf20, SLC8A2, and CTNND2 gene regions that we previously identified as possibly associated with postoperative analgesia after orthognathic surgery. We investigated associations between these SNPs and postoperative analgesia in 112 patients who underwent major open abdominal surgery in hospitals and were treated with analgesics, including opioids, after surgery. Total genomic DNA was extracted from peripheral blood or oral mucosa samples for genotyping each SNP. Effects of these potent SNPs on gene expression in the brain were also investigated in samples that were provided by the Stanley Foundation Brain Bank. In the association studies, carriers of the G allele of the rs12496846 SNP in the C3orf20 gene region were significantly associated with greater 24 h postoperative analgesic requirements among the three SNPs that were investigated (p = 0.0015), which corroborated a previous study of orthognathic patients (p < 0.0001). In the gene expression analysis, carriers of the G allele of the rs12496846 SNP were significantly associated with lower mRNA expression of the C3orf20 gene (p < 0.0001). These results indicate that this SNP could serve as a marker that predicts analgesic requirements. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the effects of end-tidal carbon dioxide tension (ETCO2) changes during remifentanil infusion on mandibular bone marrow tissue blood flow (BBF), masseter muscle tissue blood flow (MBF), mandibular bone marrow tissue oxygen tension (PbO2) and masseter muscle tissue oxygen tension (PmO2) in rabbits. Methods: Ten male tracheotomized Japan White rabbits were anesthetized and ventilated with sevoflurane. ETCO2 was adjusted to 30 mmHg. After baseline measurement, CO2 was added to the inhaled air, and ETCO2 was increased to 40 and 60 mmHg. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), BBF, MBF, PbO2, and PmO2 were recorded with and without remifentanil infusion at 0.4 µg/kg/min. Results: Two-way repeated measures analysis of variance showed no interaction between ETCO2 and remifentanil in all variables. Remifentanil infusion produced decreases in HR, SBP, MAP, BBF and MBF compared with those without remifentanil infusion, while it did not affect DBP, PbO2 and PmO2. Elevation of ETCO2 from 30 to 60 mmHg produced decreases in HR and MBF, and increases in SBP, DBP, MAP and BBF, while it did not affect PbO2 and PmO2. Conclusion: PbO2 and PmO2 remained unchanged despite changes in BBF and MBF during ETCO2 change with or without remifentanil infusion. [ABSTRACT FROM AUTHOR]

Pain-related somatosensory-evoked magnetic fields (pain-SEFs) in the cerebral cortex are mainly detected in the secondary somatosensory cortex (SII) and the cingulate gyrus. However, there are no magnetoencephalography (MEG) studies that report the effects of analgesic agents on pain-SEFs. We therefore recorded the pain-SEFs, following CO2 laser painful stimulation at 0.8 W on a trigeminally innervated skin region, and investigated the effects of ketamine hydrochloride (0.2 mg/kg IV), an N-methyl-d-aspartate (NMDA) receptor antagonist, on pain-SEFs in five healthy volunteers. Immediately after each recording, the magnitude of pain sensation was evaluated on a visual analogue scale (VAS). The equivalent current dipoles (ECDs) of pain-SEFs, following CO2 laser painful stimulation, were estimated in the SII in the contralateral hemisphere with about 100-ms latency. Ketamine reversibly inhibited pain-SEFs and decreased VAS. The result suggests that ketamine blocked the NMDA receptors in the nociceptive relay station involved in the trigeminal caudal subnucleus, resulting in the reduction of cortical activation in the SII. [Copyright &y& Elsevier]

Background: Opioids are widely used as effective analgesics, but opioid sensitivity varies widely among individuals. The underlying genetic and nongenetic factors are not fully understood. Based on the results of our previous genome‐wide association study, we investigated the effects of single nucleotide polymorphisms (SNPs) of the astrotactin 2 (ASTN2) gene on pain‐related phenotypes in surgical patients. Methods: We investigated the effects of two SNPs, rs958804 T/C and rs7858836 C/T, of the ASTN2 gene on eight and seven pain‐related phenotypes in 350 patients who underwent laparoscopic colectomy (LAC) and 358 patients who underwent mandibular sagittal split ramus osteotomy (SSRO), respectively. In both surgical groups, intravenous fentanyl patient‐controlled analgesia (PCA) was used for postoperative analgesia, and 24‐hour postoperative PCA fentanyl use was the primary endpoint. Results: The association analyses among the two SNPs and pain‐related traits showed that 24‐hour fentanyl use was significantly associated with the two SNP genotypes in both surgical groups. The Mann‐Whitney test showed that 24‐hour fentanyl use was lower in patients with the C allele than in patients with the TT genotype of the rs958804 T/C SNP (P =.0019 and.0200 in LAC and SSRO patients, respectively), and it was lower in patients with the T allele than in patients with the CC genotype of the rs7858836 C/T SNP (P =.0017 and.0098 in LAC and SSRO patients, respectively). Conclusion: The two SNPs of the ASTN2 gene were consistently associated with fentanyl requirements after two different types of surgery. These findings may contribute to personalized pain control. [ABSTRACT FROM AUTHOR]

Cranial neural crest cells are multipotent cells that migrate into the pharyngeal arches of the vertebrate embryo and differentiate into various craniofacial organ derivatives. Therefore, migrating cranial neural crest cells are considered one of the most attractive candidate cell sources in regenerative medicine. We generated cranial neural crest like cell (cNCCs) using mouse-induced pluripotent stem cells cultured in neural crest-inducing medium for 14 days. Subsequently, we conducted RNA sequencing experiments to analyze gene expression profiles of cNCCs at different time points after induction. cNCCs expressed several neural crest specifier genes; however, some previously reported specifier genes such as paired box 3 and Forkhead box D3, which are essential for embryonic neural crest development, were not expressed. Moreover, ETS proto-oncogene 1, transcription factor and sex-determining region Y-box 10 were only expressed after 14 days of induction. Finally, cNCCs expressed multiple protocadherins and a disintegrin and metalloproteinase with thrombospondin motifs enzymes, which may be crucial for their migration. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HPP) is a congenital disorder caused by mutations in the tissue-nonspecific alkaline phosphatase (TNALP) gene. The pathogenesis of HPP varies, ranging from severe cases in which there is total absence of fetal bone calcification, which leads to stillbirth, to relatively mild cases in which the effects are confined to the teeth, such as early loss of the primary teeth. In recent years, the establishment of enzyme supplementation as a treatment method has prolonged survival in patients; however, this approach does not provide sufficient improvement for failed calcification. Furthermore, the effects of enzyme replacement therapy on the jawbone and periodontal tissues have not yet been studied in detail. Therefore, in this study, we investigated the therapeutic effects of enzyme replacement therapy on jawbone hypocalcification in mice. Recombinant TNALP was administered to mothers before birth and newborns immediately after birth, and the effect of treatment was evaluated at 20 days of age. The treated HPP mice had improved mandible (mandibular length and bone quality) and tooth quality (root length of mandibular first molar, formation of cementum), as well as improved periodontal tissue structure (structure of periodontal ligament). Furthermore, prenatal treatment had an additional therapeutic effect on the degree of mandible and enamel calcification. These results suggest that enzyme replacement therapy is effective for the treatment of HPP, specifically in the maxillofacial region (including the teeth and mandible), and that early initiation of treatment may have additional beneficial therapeutic effects. [ABSTRACT FROM AUTHOR]

Various stimuli induce pain when applied to the surface of exposed dentin. However, the mechanisms underlying dentinal pain remain unclear. We investigated intercellular signal transduction between odontoblasts and trigeminal ganglion (TG) neurons following direct mechanical stimulation of odontoblasts. Mechanical stimulation of single odontoblasts increased the intracellular free calcium concentration ([Ca]) by activating the mechanosensitive-transient receptor potential (TRP) channels TRPV1, TRPV2, TRPV4, and TRPA1, but not TRPM8 channels. In cocultures of odontoblasts and TG neurons, increases in [Ca] were observed not only in mechanically stimulated odontoblasts, but also in neighboring odontoblasts and TG neurons. These increases in [Ca] were abolished in the absence of extracellular Ca and in the presence of mechanosensitive TRP channel antagonists. A pannexin-1 (ATP-permeable channel) inhibitor and ATP-degrading enzyme abolished the increases in [Ca] in neighboring odontoblasts and TG neurons, but not in the stimulated odontoblasts. G-protein-coupled P2Y nucleotide receptor antagonists also inhibited the increases in [Ca]. An ionotropic ATP (P2X) receptor antagonist inhibited the increase in [Ca] in neighboring TG neurons, but not in stimulated or neighboring odontoblasts. During mechanical stimulation of single odontoblasts, a connexin-43 blocker did not have any effects on the [Ca] responses observed in any of the cells. These results indicate that ATP, released from mechanically stimulated odontoblasts via pannexin-1 in response to TRP channel activation, transmits a signal to P2X receptors on TG neurons. We suggest that odontoblasts are sensory receptor cells and that ATP released from odontoblasts functions as a neurotransmitter in the sensory transduction sequence for dentinal pain. [ABSTRACT FROM AUTHOR]

A decrease in arterial carbon dioxide tension induces an increase in masseter muscle blood flow and a decrease in mandibular bone marrow blood flow during general anesthesia. In addition, dexmedetomidine infusion reduces oral tissue blood flow. In this study we investigated how end-tidal carbon dioxide tension (ET-CO2) changes influence on oral tissue blood flow during continuous dexmedetomidine infusion in rabbits. Eleven male Japan White rabbits were anesthetized with sevoflurane. Then, ET- CO2 was set at 30 mmHg and adjusted to 40 and 60 mmHg, and heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, common carotid artery blood flow, mandibular bone marrow blood flow, masseter muscle blood flow, and blood flow in other oral tissues were measured. Following this, the ET- CO2 was returned to 30 mmHg and dexmedetomidine was infused over 60 min. The measurements were repeated. Most parameters increased, regardless of whether or not dexmedetomidine was present, and heart rate and masseter muscle blood flow decreased in an ET- CO2-dependent manner. Dexmedetomidine infusion suppressed ET-CO2-dependent masseter muscle blood flow change. Masseter muscle blood flow during ET- CO2 at 30 mmHg with dexmedetomidine was the same as that during ET- CO2 at 40 mmHg without dexmedetomidine. Our findings suggest that dexmedetomidine infusion and slight hypocapnia under general anesthesia suppress an increase in masseter muscle blood flow as well as reducing mandibular bone marrow blood flow. These results may be of significance for decreasing bleeding during oral and maxillofacial surgery. [ABSTRACT FROM AUTHOR]

Abstract: To elucidate the mechanisms of individual differences in pain and analgesic sensitivity, we analyzed the variable number of tandem repeat polymorphism in the third exon of the dopamine D4 receptor gene. Alleles that were less than four repeats long and four or more repeats long were considered Short and Long, respectively. We found that the Short/Short genotype group was significantly more sensitive to pain and less sensitive to analgesics than the Short/Long+Long/Long genotype group. Our data suggest that this polymorphism may predict individual differences in pain and analgesic sensitivity and help achieve adequate pain control in the future. [Copyright &y& Elsevier]

icardi syndrome (AS) is a rare congenital syndrome and is characterized by the triad of infantile spasm, agenesis of the corpus callosum, and anomaly of chorioretinal lacunae. We here report a case of a patient with AS under general anesthesia. Although there is no report in which muscle relaxants were used in AS patients, vecuronium bromide was used for artificial pneumoperitoneum in this case. Careful management is important for AS patients during an operation that significantly affects respiratory function. In addition, it is possible that muscle relaxants be administered safely in AS patients. Careful monitoring such as epileptiform electroencephalogram and bispectral index monitors may be needed for the early detection of epileptic activities. [ABSTRACT FROM AUTHOR]

We conducted a double-blind placebo-controlled study to investigate the effects of the intraoperative intravenous infusion of adenosine 5′-triphosphate (ATP) on intraoperative hemodynamics and postoperative pain in patients undergoing major orofacial surgery. Thirty patients (age, 16–42 years; 16 males/14 females) scheduled for sagittal split ramus osteotomy were assigned in a double-blind fashion to receive intraoperative intravenous infusion of ATP ( n = 15) or saline ( n = 15). Anesthesia was induced and maintained with propofol, fentanyl, and vecuronium. Local anesthesia was added for intraoperative analgesia. In the ATP group, ATP was infused at a rate of 160 μg·kg−1·min−1 throughout surgery. Postoperative pain was managed with intravenous patient-controlled analgesia (PCA) with morphine. The intensity of postoperative pain was assessed with a verbal numeric rating scale (NRS). Morphine consumption was also assessed. There were no differences in demographic, anesthetic, and surgical data between the ATP and placebo groups. Intraoperatively, ATP effectively suppressed responses of blood pressure and heart rate to painful surgical stimuli. There were no differences in postoperative NRS scores between the two groups. However, postoperative morphine consumption was significantly less in the ATP group, compared with the placebo group, throughout the 72-h postoperative observation period. Cumulative morphine consumption for 72 h postoperatively was 47% less with ATP, compared with placebo. No adverse effect of ATP was observed. Our data suggest that intraoperative ATP infusion can blunt hemodynamic responses to surgical stimuli and produce prolonged analgesia in patients undergoing major orofacial surgery. [ABSTRACT FROM AUTHOR]

In contrast to reports on the classical laryngeal mask airway (classical LMA; CLMA), no report has calculated the 50% and 95% effect-site concentrations (EC50 and EC95, respectively) of propofol required for flexible LMA (FLMA) insertion. This study was designed to determine the EC50 and EC95 of propofol for FLMA insertion, using probit analysis, and to investigate whether supplemental 0.25 μg·kg−1 fentanyl decreased these concentrations. Fifty-nine unpremedicated patients who were scheduled for elective minor oral surgery were randomly allocated to a saline-propofol group (S-P group; n = 30) or a fentanyl-propofol group (F-P group; n = 29). Each group was further divided into four subgroups, in which the propofol EC for FLMA insertion was set at 2.5, 3.0, 3.5, and 4.0 μg·ml−1, respectively, in the S-P group and 1.8, 2.0, 2.5, and 3.0 μg·ml−1, respectively, in the F-P group,. The experiment was assessed as ”successful” when FLMA insertion within 1 min was possible. The EC50 and EC95 in the S-P group were 3.29 (95% confidence interval [CI], 2.83–3.93) and 4.73 (95% CI, 3.94–12.22) μg·ml−1, and those in the F-P group were 2.13 (95% CI, 1.42–2.60) and 3.54 95% CI, (2.78-34.78) μg·ml−1, respectively. The EC50 in the F-P group was significantly lower than that in the S-P group. There were no significant differences in bispectral index (BIS), hemodynamic variables, respiratory rate, and arterial oxygen saturation ( $$ Sp_{O_2 } $$) between the S-P and F-P groups. The propofol EC50 for FLMA insertion was decreased by supplemental 0.25 μg·kg−1 fentanyl without BIS, hemodynamic, or respiratory depression. [ABSTRACT FROM AUTHOR]

Abstract: To clarify the topography of the areas representing whole intraoral structures and elucidate bilateral neuronal projection to those areas in the primary somatosensory (S1) cortex, we recorded somatosensory-evoked magnetic fields (SEFs), which reflect the earliest cortical responses to pure tactile stimulation, using magnetoencephalography and a piezo-driven tactile stimulation device. Subjects consisted of 10 healthy male adults. Following tactile stimulation of 6 sites on the oral mucosa (inferior/superior buccal mucosa, posterior/anterior tongue mucosa, and upper/lower lip mucosa), SEFs with a peak latency of 15 ms (1M) were identified bilaterally. In contrast, SEFs with a peak latency of 30 ms following right index finger tactile stimulation were identified only in the contralateral hemisphere. Equivalent current dipoles (ECDs) generating 15 ms components were found along the posterior wall of the central sulcus, bilaterally. The ECD locations for oral mucosa-representing areas were located inferiorly to those for the index finger, with the following pattern of organization from top to bottom along the central sulcus: index finger, upper or lower lip, anterior or posterior tongue and superior or inferior buccal mucosa, with a wide distribution, covering 30% of the S1 cortex. Source strength for 1M in the ipsilateral hemisphere was weaker than that in the contralateral hemisphere. These results clearly indicate that sensory afferents innervating the intraoral region project to both the contralateral and ipsilateral 3b areas via the trigeminothalamic tract, where contralateral projection is predominant. The results clarify the intraoral structure-representing areas in the S1 cortex, adding those areas to the classical “sensory homunculus”. [Copyright &y& Elsevier]

Abstract: A variety of pharmacological agents are clinically used to treat pain-related diseases, including in the orofacial region. The effects of analgesics upon cerebral sites responsible for pain perception have yet to be determined. The aim of the present study was to examine the effects of ketamine, an N-methyl-d-aspartate (NMDA) antagonist, and fentanyl, a narcotic analgetic, on pain-related somatosensory-evoked magnetic fields (pain-SEFs) induced by CO2 laser stimulation of the trigeminally innervated area. Two peaks with latencies of approximately 120 and 200ms were observed in pain-SEFs after CO2 laser stimulation. Peaks with approximately 120ms latency were detected in the bilateral secondary somatosensory cortices. Amplitude of pain-SEFs after CO2 laser stimulation increased in an intensity-dependent manner. Ketamine suppressed amplitude and prolonged latency of pain-SEFs, whilst fentanyl did not. This suggests that ketamine inhibits NMDA receptor-mediated neurotransmission in a pain input pathway to the cerebral cortex, thereby exerting an analgesic effect. Fentanyl, which acts via opioid receptors, is believed to act differently to ketamine in the pain input process. [Copyright &y& Elsevier]

Chronic orofacial pain is often refractory to conventional pain therapies. We conducted an open-label study to determine whether adenosine 5′-triphosphate (ATP) could alleviate chronic intractable orofacial pain, and if so, which type of pain could respond to ATP. In 8 and 16 patients with non-neuropathic and neuropathic intractable orofacial pain, respectively, ATP was intravenously infused at a rate of 100 µg·kg−1·min−1 over 120 min. The magnitudes of spontaneous pain and brush-evoked allodynia were graded with a visual analog scale (VAS). When a VAS score for spontaneous pain was decreased by 50% or more by ATP, the patient was classified as a responder. The patients could be clearly divided into 10 responders and 14 non-responders. Ten of the 16 patients (62.5%) with neuropathic pain, but none of the 8 patients with non-neuropathic pain, responded to ATP. In particular, all of 8 patients with neuropathic pain following pulpectomy, with or without subsequent tooth extraction, responded to ATP. In the 10 responders, VAS scores for spontaneous pain decreased slowly but progressively during the infusion period, and eventually, ATP reduced the VAS scores for spontaneous pain and allodynia by 82 ± 15% and 74 ± 9%, respectively. In these responders, the analgesic and anti-allodynic effects of ATP outlasted the infusion period for medians of 7 and 12 h, respectively. Intravenous ATP did not relieve non-neuropathic orofacial pain. However, it exerted slowly expressed but long-lasting analgesic and anti-allodynic effects in patients with neuropathic orofacial pain, especially in those suffering from neuropathic pain following pulpectomy and/or tooth extraction. [ABSTRACT FROM AUTHOR]

Translocator protein (TSPO) is a mitochondrial outer membrane protein expressed on a variety of immune cells, including macrophages, dendritic cells, and T cells, in addition to neurons and steroid-producing cells. Previous studies of TSPO ligands have suggested that TSPO is involved in multiple cellular functions, including steroidogenesis, immunomodulation, and cell proliferation. Currently, there are limited reports on the effects of TSPO or TSPO ligands on T cell-mediated immune responses. We here investigated the involvement of TSPO/TSPO ligand in T cell responses using a 2,4-dinitro-1-fluorobenzene (DNFB)-induced contact hypersensitivity (CH) model. Treatment with Ro5-4864, a TSPO ligand, during DNFB sensitization reduced the number and activation status of CD4+ and CD8+ T cells in draining lymph nodes and alleviated skin inflammation after DNFB challenge. Adoptive transfer of Ro5-4864-treated mouse-derived DNFB-sensitized T cells to naïve mice inhibited CH responses after DNFB challenge. Ro5-4864-treated sensitized T cells showed lower proliferative responses when stimulated with DNFB-pulsed antigen-presenting cells compared to control-treated sensitized T cells. Ro5-4864 also suppressed cell proliferation, as well as adenosine triphosphate and lactate production, during T cell activation. Moreover, the inhibitory effects of Ro5-4864 on T cell responses were conserved in TSPO-deficient cells. Our results suggest that Ro5-4864 inhibits CH responses by suppressing energy metabolism, at least via glycolysis, to reduce the T cell primary response in a TSPO-independent manner., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Midazolam is widely used for intravenous sedation. However, wide interindividual variability is seen in the sensitivity to midazolam. The association between genetic factors and interindividual differences in midazolam sensitivity remains unclear. The present study explored the association between common genetic variants and sedative and amnesic effects of midazolam. This prospective study included patients who were scheduled to undergo dental procedures under intravenous sedation. The sedative effect was evaluated using the Ramsay sedation scale 5 min after midazolam (0.05 mg/kg) administration. We employed two parallel approaches in this study: genome-wide approach and candidate gene approach. The γ-aminobutyric acid type A receptor subunit genes were selected as candidate genes. Multivariate linear regression analyses were performed to investigate the association between the Ramsay sedation scale and genetic variants. We also analyzed the association between the presence of anterograde amnesia and genetic variants using multivariate binominal logistic regression analyses. The analyses were adjusted for potential confounding factors. A total of 191 patients were included in the analyses. In the genome-wide association analyses, no significant association was found between the genetic variants and Ramsay scores. In the candidate gene analyses, the rs73247636 (dominant model: β = 0.72 [95% confidence interval, 0.34 to 1.10], P < 0.001) and rs56278524 (dominant model: β = 0.73 [0.37 to 1.10], P < 0.001) polymorphisms of the GABRB1 gene were significantly associated with Ramsay scores. Additionally, the rs73247636 (dominant model: odds ratio [OR] = 8.39 [2.36 to 29.85], P = 0.001) and rs56278524 (dominant model: OR = 15.26 [3.42 to 68.07], P < 0.001) polymorphisms were also significantly associated with the presence of anterograde amnesia. The rs73247636 and rs56278524 single-nucleotide polymorphisms of GABRB1 were associated with the sedative and amnesic effects of midazolam., (© 2024. The Author(s).)

Cardiac ischemia, such as angina pectoris or myocardial infarction, is associated with pain in the oral cavity, lower jaw, head, or neck, or spanning from the left upper arm to the shoulder. When presenting to a dentist, however, appropriate treatment for such patients is often delayed, as dental problems are usually the first to be suspected when the chief complaint is orofacial pain. This report describes a case of a 70-year-old woman who was aware of pain and a burning sensation in the oral cavity upon exertion for a year prior to presenting at our clinic. She had been examined by her family physician, an otolaryngologist, and another dentist, none of whom found any abnormalities other than suspected periodontal disease and caries, for which she was treated. An examination at our clinic revealed no abnormal dental findings that would have been consistent with the mandibular pain, however. Although no chest symptoms were reported, pain was elicited on exertion, suggesting cardiogenic toothache. An immediate referral to a cardiologist was therefore made on the same day. The patient visited the cardiology department of the University Hospital of Tokyo Dental College 6 days later. The increased frequency of symptoms on exertion suggested unstable angina, and the patient was admitted to the emergency department on the same day. Emergency coronary angiography showed that right coronary artery #1 was 99% stenosed proximally (highly calcified plaque). The diagnosis was unstable angina pectoris, with the right coronary artery #1 as the responsible lesion, and percutaneous coronary angioplasty was performed on the same day. Subsequently, all the orofacial pain disappeared, confirming unstable angina as the cause. The pain characteristics in this case were consistent with pain associated with cardiac ischemia, which led to the immediate referral to the cardiology department. In cases of toothache associated with cardia ischemia, it is essential to seek cardiological care as soon as possible.

Background: This study evaluated the effect of remimazolam and propofol on changes in autonomic nerve activity caused by surgical stimulation during orthognathic surgery, using power spectrum analysis of blood pressure variability (BPV) and heart rate variability (HRV), and their respective associations with cardiovascular fluctuations., Methods: A total of 34 patients undergoing Le Fort I osteotomy were randomized to the remimazolam (Group R, 17 cases) or propofol (Group P, 17 cases) groups. Observables included the low-frequency component of BPV (BPV LF; index of vasomotor sympathetic nerve activity), high-frequency component of HRV (HRV HF; index of parasympathetic nerve activity), balance index of the low- and high-frequency components of HRV (HRV LF/HF; index of sympathetic nerve activity), heart rate (HR), and systolic blood pressure (SBP). Four observations were made: (1) baseline, (2) immediately before down-fracture, (3) down-fracture, and (4) 5 min after down-fracture. Data from each observation period were compared using a two-way analysis of variance with a mixed model. A Bonferroni multiple comparison test was performed in the absence of any interaction. One-way analysis of variance followed by Tukey's multiple comparisons test was performed when a significant interaction was observed between time and group, with P < 0.05 indicating statistical significance., Results: Evaluation of autonomic nerve activity in comparison with baseline during down-fracture showed a significant increase in BPV LF (P < 0.001), an increasing trend in HRV LF/HF in Group P, and an increasing trend in HRV HF in Group R. There were no significant differences in HR or SBP between the two groups., Conclusion: During down-fracture of Le Fort I osteotomy, sympathetic nerve activity was predominant with propofol anesthesia, and parasympathetic nerve activity was predominant with remimazolam anesthesia., Competing Interests: CONFLICTS OF INTERESTS: The authors declare no conflicts of interest., (Copyright © 2024 Journal of Dental Anesthesia and Pain Medicine.)

Objective: This study aimed to evaluate the incidence of early (up to 2 h) and late (2-24 h) postoperative nausea and vomiting (PONV) and hypotension in patients who underwent general anesthesia for orthognathic surgery using propofol or remimazolam along with remifentanil., Methods: This retrospective chart review included healthy adult patients under the age of 60 who underwent orthognathic surgery using propofol (P group) or remimazolam (R group) from January 2021 to March 2022. Records were reviewed to gather PONV and intraoperative hypotension data as well as patient characteristics and other variables., Results: Early PONV was significantly lower in the P group vs the R group (9.5% vs 34.1%, respectively; P = .002), although the difference in late PONV was insignificant (36.9% vs 51.2%, respectively; P = .13). A higher incidence of intraoperative hypotension was noted in the P group (22.6%) vs the R group (2.4%; P = .004); however, there were no differences in average intraoperative systolic blood pressure or vasopressor administration., Conclusion: These results suggest that propofol is associated with a lower incidence of early PONV as compared to remimazolam; however, antiemetics are still recommended given the frequency of late PONV in both groups. Propofol also caused more episodes of intraoperative hypotension vs remimazolam, but the increase in transient hypotension is likely to be irrelevant during orthognathic surgery in healthy adults under the age of 60.

Negative pressure pulmonary edema (NPPE) can occur rapidly after the release of an upper airway obstruction. In general anesthesia, NPPE can be caused by laryngospasm after extubation. This report describes a case in which NPPE was thought to have occurred after extubation during general anesthesia in a disabled person. The patient was a 28-yearold man, 160 cm in height and 56 kg in weight, who was scheduled for dental caries treatment under ambulatory general anesthesia due to intellectual disability. After induction of general anesthesia, nasal intubation was performed after sufficient oral suctioning to remove a large amount of serous secretion. After completion of dental treatment, pressurized extubation was performed after oral suctioning as sufficient spontaneous breathing and body movement were observed. Immediately after extubation, SpO 2 dropped to 80%, subsequently recovering to 99% under oxygen administration at 5 liter/min with an oxygen mask. It dropped to approximately 85% again, however, when administration of oxygen was discontinued. Although communication with the patient was difficult, no expression of anguish or dyspnea was observed. A chest radiograph showed symmetric middle-lobe and lingular segment infiltrates, and the patient was transferred to the nearest general hospital. No obvious clinical findings other than a decrease in SpO 2 were observed, suggesting NPPE as a result of airway narrowing due to secretions.

Objective: This study investigated the involvement of α1- and β2-adrenergic receptors in skeletal muscle blood flow changes during variations in ETCO2., Methods: Forty Japanese White rabbits anesthetized with isoflurane were randomly allocated to 1 of 5 groups: phentolamine, metaproterenol, phenylephrine, butoxamine, and atropine. Heart rate (HR), systolic blood pressure (SBP), common carotid artery blood flow (CCBF), masseter muscle tissue blood flow (MBF), and quadriceps muscle tissue blood flow (QBF) were recorded and analyzed at 3 periods: (1) baseline, (2) during hypercapnia (phentolamine and metaproterenol groups) or hypocapnia (phenylephrine, butoxamine, and atropine groups), and (3) during or after receiving vasoactive agents., Results: MBF and QBF decreased during hypercapnia. The decrease in MBF was smaller than that in QBF. SBP and CCBF increased, while HR decreased. Both MBF and QBF recovered to their baseline levels after phentolamine administration. MBF became greater than its baseline level, while QBF did not fully recover after metaproterenol administration. MBF and QBF increased during hypocapnia. The increase rate in MBF was larger than that in QBF. HR, SBP, and CCBF did not change. Both MBF and QBF decreased to ∼90% to 95% of their baseline levels after phenylephrine or butoxamine administration. Atropine showed no effects on MBF and QBF., Conclusion: These results suggest the skeletal muscle blood flow changes observed during hypercapnia and hypocapnia may mainly involve α1-adrenergic but not β2-adrenergic receptor activity., (© 2023 by the American Dental Society of Anesthesiology.)

Background: This study aimed to investigate the relationship between pharyngeal morphology and the success or failure of blind nasotracheal intubation using standard lateral cephalometric radiography and to analyze the measurement items affecting the difficulty of blind nasotracheal intubation., Methods: Assuming a line perpendicular to the Frankfort horizontal (FH) plane, the reference point (O) was selected 1 cm above the posterior-most end of the hard palate. A line passing through the reference point and parallel to the FH plane is defined as the X-axis, and a line passing through the reference point and perpendicular to the X-axis is defined as the Y-axis. The shortest length between the tip of the uvula and posterior pharyngeal wall (AW), shortest length between the base of the tongue and posterior pharyngeal wall (BW), and width of the glottis (CW) were measured. The midpoints of the lines representing each width are defined as points A, B, and C, and the X and Y coordinates of each point are obtained (AX, BX, CX, AY, BY, and CY). For each measurement, a t-test was performed to compare the tracheal intubation success and failure groups. A binomial logistic regression analysis was performed using clinically relevant items., Results: The items significantly affecting the success rate of blind nasotracheal intubation included the difference in X coordinates at points A and C (Odds ratio, 0.714; P-value, 0.024) and the ∠ABC (Odds ratio, 1.178; P-value, 0.016)., Conclusion: Using binomial logistic regression analysis, we observed statistically significant differences in AX-CX and ∠ABC between the success group and the failure group., Competing Interests: CONFLICT OF INTEREST: The authors declare no conflict of interest., (Copyright © 2022 Journal of Dental Anesthesia and Pain Medicine.)

Trigeminal neuralgia occurs in the orofacial region, characteristically causing pain that feels like a transient electric shock. Some histopathological studies have reported that trigeminal neuralgia is caused by mechanical compression of the demyelinated trigeminal nerve; the pathophysiological mechanism behind this phenomenon remains to be clarified, however. Cell-cell interactions have also been reported to be involved in the development and modulation of some types of neuropathic pain. The purpose of this study was to investigate the potential contribution of cell-cell interactions to trigeminal neuralgia by measuring intracellular free Ca 2+ concentrations ([Ca 2+ ] i ) in primary cultured trigeminal ganglion (TG) cells. Direct mechanical stimulation of TG cells induced an increase in [Ca 2+ ] i in both neuronal and non-neuronal cells, such as glial cells. Moreover, this increase was stimulus intensity-dependent and non-desensitizing. Direct mechanical stimulation increased [Ca 2+ ] i in neighboring cells as well, and this increase was inhibited by application of carbamazepine. These results indicate that direct mechanical stimulation affects Ca 2+ signaling. Trigeminal ganglion cells establish intercellular networks between themselves, suggesting that this is involved in the development and generation of trigeminal neuralgia.

Post-traumatic trigeminal neuropathic pain is mainly caused by the extraction of third molars or the placement of dental implants. This report describes the treatment of neuropathic pain arising after guided tissue regeneration (GTR). The patient was a 55-year-old woman who had to undergo GTR due to severe periodontitis in the distal aspect of the right mandibular second molar. Postoperatively, the patient had been prescribed mecobalamin for hypesthesia and allodynia in the right lower lip. No improvement was observed in these symptoms after 4 months, however, so she was referred to our Orofacial Pain Center. Preoperative and postoperative cone-beam computed tomography revealed a cyst-like lesion (radiolucent area) close to the right mandibular second molar and canal. Although the results of quantitative sensory examination were normal, rubbing the right lower lip with a cotton swab elicited mechanical allodynia. The diagnosis was post-traumatic trigeminal neuropathic pain for which the patient was given pregabalin and Neurotropin ® . The symptoms improved within approximately 32 weeks, with the medication being terminated at 64 weeks. Although hypoesthesia due to nerve injury may suddenly go into remission, allodynia is often intractable. If symptoms show no improvement after 3 months, possible nerve injury should be investigated. Additionally, the distal root of the mandibular molar may be close to the inferior alveolar nerve, necessitating appropriate diagnostic imaging of the operative field. If the lesion or distal root is close to the inferior alveolar nerve, postoperative hypesthesia or neuropathic pain may occur, even without direct trauma.

Serum serves as a source of rich nutrients during in vitro cell culture, facilitating cell adhesion, growth, and differentiation. When culturing stem cells for transplantation, however, it must be remembered that such culture medium may contain substances potentially harmful to the proposed recipient and may even induce cellular damage. The purpose of this study was to determine whether KnockOut Serum Replacement (KSR), a chemically defined medium supplement, enhanced in vitro differentiation of induced pluripotent stem cells into odontoblasts. Cranial neural crest cells, precursors of odontoblasts, were generated from mouse-induced pluripotent stem cells. They were then cultured in serum-free Dulbecco's modified Eagle's/F12 medium containing fibroblast growth factor 8 with or without KSR. The cells cultured with KSR showed strong proliferation, acquired a spindle-like morphology, and connected with the surrounding cells. KnockOut Serum Replacement also boosted expression of odontoblast markers as measured by qRT-PCR, and increased dentin sialoprotein as assessed by immunostaining. These results confirmed that mouse-induced pluripotent stem cells differentiated into odontoblasts under serum-free conditions, and that KSR enhanced the efficiency of this process.

Short tandem repeats (STRs) and variable number of tandem repeats (VNTRs) that have been identified at approximately 0.7 and 0.5 million loci in the human genome, respectively, are highly multi-allelic variations rather than single-nucleotide polymorphisms. The number of repeats of more than a few thousand STRs was associated with the expression of nearby genes, indicating that STRs are influential genetic variations in human traits. Analgesics act on the central nervous system via their intrinsic receptors to produce analgesic effects. In the present study, we focused on STRs and VNTRs in the CNR1 , GRIN2A , PENK , and PDYN genes and analyzed two peripheral pain sensation-related traits and seven analgesia-related traits in postoperative pain management. A total of 192 volunteers who underwent the peripheral pain sensation tests and 139 and 252 patients who underwent open abdominal and orthognathic cosmetic surgeries, respectively, were included in the study. None of the four STRs or VNTRs were associated with peripheral pain sensation. Short tandem repeats in the CNR1 , GRIN2A , and PENK genes were associated with the frequency of fentanyl use, fentanyl dose, and visual analog scale pain scores 3 h after orthognathic cosmetic surgery (Spearman's rank correlation coefficient ρ = 0.199, p = 0.002, ρ = 0.174, p = 0.006, and ρ = 0.135, p = 0.033, respectively), analgesic dose, including epidural analgesics after open abdominal surgery ( ρ = -0.200, p = 0.018), and visual analog scale pain scores 24 h after orthognathic cosmetic surgery ( ρ = 0.143, p = 0.023), respectively. The associations between STRs in the CNR1 gene and the frequency of fentanyl use and fentanyl dose after orthognathic cosmetic surgery were confirmed by Holm's multiple-testing correction. These findings indicate that STRs in the CNR1 gene influence analgesia in the orofacial region., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kasai, Nishizawa, Hasegawa, Fukuda, Ichinohe, Nagashima, Hayashida and Ikeda.)

Objective: The aim of this study was to investigate the changes in pulpal blood flow (PBF) and pulpal oxygen tension (PpulpO2) after injecting local anesthetics with vasoconstrictors., Methods: Under general anesthesia, male Japanese White rabbits were injected with 0.6 mL of 2% lidocaine with 1:80,000 epinephrine (LE) or 3% propitocaine (prilocaine) with 0.03 IU felypressin (PF) at the apical area of the lower incisor., Results: Relative to baseline, PBF and PpulpO2 significantly decreased 5 minutes after LE or PF injection as compared with saline. The decrease in PBF was significantly lower in the LE group than in the PF group. Although the LE group had a larger decrease in PpulpO2 relative to baseline than the PF group did, that difference was not significant. PBF and PpulpO2 recovered to baseline faster in the PF group than in the LE group., Conclusion: The injection of local anesthetic solutions containing vasoconstrictors (LE or PF) transiently caused significant decreases in PBF that resulted in significant decreases in PpulpO2. The recovery of PpulpO2 was faster than PBF regardless of the vasoconstrictor used., (© 2021 by the American Dental Society of Anesthesiology.)

Odontoblasts play critical roles in dentin formation and sensory transduction following stimuli on the dentin surface. Exogenous stimuli to the dentin surface elicit dentinal sensitivity through the movement of fluids in dentinal tubules, resulting in cellular deformation. Recently, Piezo1 channels have been implicated in mechanosensitive processes, as well as Ca 2+ signals in odontoblasts. However, in human odontoblasts, the cellular responses induced by mechanical stimulation, Piezo1 channel expression, and its pharmacological properties remain unclear. In the present study, we examined functional expression of the Piezo1 channel by recording direct mechanical stimulation-induced Ca 2+ signaling in dentin matrix protein 1 (DMP-1)-, nestin-, and dentin sialophosphoprotein (DSPP)-immunopositive human odontoblasts. Mechanical stimulation of human odontoblasts transiently increased intracellular free calcium concentration ([Ca 2+ ] i ). Application of repeated mechanical stimulation to human odontoblasts resulted in repeated transient [Ca 2+ ] i increases, but did not show any desensitizing effects on [Ca 2+ ] i increases. We also observed a transient [Ca 2+ ] i increase in the neighboring odontoblasts to the stimulated cells during mechanical stimulation, showing a decrease in [Ca 2+ ] i with an increasing distance from the mechanically stimulated cells. Application of Yoda1 transiently increased [Ca 2+ ] i . This increase was inhibited by application of Gd 3+ and Dooku1, respectively. Mechanical stimulation-induced [Ca 2+ ] i increase was also inhibited by application of Gd 3+ or Dooku1. When Piezo1 channels in human odontoblasts were knocked down by gene silencing with short hairpin RNA (shRNA), mechanical stimulation-induced [Ca 2+ ] i responses were almost completely abolished. Piezo1 channel knockdown attenuated the number of Piezo1-immunopositive cells in the immunofluorescence analysis, while no effects were observed in Piezo2-immunopositive cells. Alizarin red staining distinctly showed that pharmacological activation of Piezo1 channels by Yoda1 significantly suppressed mineralization, and shRNA-mediated knockdown of Piezo1 also significantly enhanced mineralization. These results suggest that mechanical stimulation predominantly activates intracellular Ca 2+ signaling via Piezo1 channel opening, rather than Piezo2 channels, and the Ca 2+ signal establishes intercellular odontoblast-odontoblast communication. In addition, Piezo1 channel activation participates in the reduction of dentinogenesis. Thus, the intracellular Ca 2+ signaling pathway mediated by Piezo1 channels could contribute to cellular function in human odontoblasts in two ways: (1) generating dentinal sensitivity and (2) suppressing physiological/reactional dentinogenesis, following cellular deformation induced by hydrodynamic forces inside dentinal tubules., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Matsunaga, Kimura, Ouchi, Nakamura, Ohyama, Ando, Nomura, Azuma, Ichinohe and Shibukawa.)

The objectives of this research were to investigate (a) what was the most effective infusion rate of remifentanil and (b) the degree to which sympathomimetic effects were involved with cardiovascular stimulation by using a power spectral analysis of heart rate variability (HRV). A total of 63 healthy individuals scheduled for sagittal split ramus osteotomy were enrolled and randomly allocated to 1 of 3 groups: remifentanil infusion rate of 0.1, 0.2, or 0.4 μg/kg/min. Anesthesia was maintained with remifentanil and propofol. Before the surgical procedure, 2% lidocaine containing 12.5 μg/mL epinephrine was administered in the surgical field for local anesthesia. Systolic blood pressure (SBP), heart rate (HR), low-frequency (LF) and high-frequency (HF) components in HRV power spectral analysis, and the LF/HF ratio were analyzed. Increases in SBP and HR were observed after local anesthesia in all 3 groups, but no significant differences were observed between the groups. Remifentanil infusion at 0.1 μg/kg/min may be appropriate to minimize cardiovascular stimulation caused by exogenous epinephrine from local anesthesia. Although a rise in the LF/HF ratio was observed after local anesthesia in all groups, no relationship was observed between the cardiovascular changes and the increase in LF/HF ratio. This suggests that sympathomimetic effects are involved to a lesser extent with the cardiovascular stimulation caused by exogenous epinephrine., (© 2021 by the American Dental Society of Anesthesiology.)

The aim of this study was to compare changes in tissue blood flow and tissue oxygen tension in the masseter muscle and mandibular bone marrow induced by remifentanil under desflurane or sevoflurane anesthesia. Eleven male tracheotomized Japan White rabbits were anesthetized with desflurane or sevoflurane under mechanical ventilation. The order of the inhalation of desflurane or sevoflurane was randomized. Desflurane or sevoflurane was administered at 1.0 minimum alveolar concentration and remifentanil was infused at 0.4 µg/kg/min. Observed variables included heart rate (HR), blood pressure (BP), common carotid artery blood flow (CCBF), mandibular bone marrow tissue blood flow (BBF), masseter muscle tissue blood flow (MBF), mandibular bone marrow tissue oxygen tension (PbO 2 ), and masseter muscle tissue oxygen tension (PmO 2 ). Two way repeated measures ANOVA showed no interaction between volatile anesthetics and remifentanil infusion except for MBF. There were significant differences in HR, SBP, DBP, MAP and CCBF between desflurane and sevoflurane groups. There were also significant differences in HR, SBP, DBP, MAP, CCBF, BBF and PbO 2 before, during and after remifentanil infusion. Desflurane reduced tissue blood flow in the masseter muscle and mandibular bone marrow while better maintained HR and BP than sevoflurane. Under remifentanil infusion, although both anesthetics reduced tissue blood flow, tissue oxygen tension was maintained in masseter muscle and mandibular bone marrow.

Bradykinin (BK) and its receptors, B 1 and B 2 , in trigeminal ganglion (TG) neurons are involved in the regulation of pain. Recent studies have revealed that B 1 receptors are expressed in neonatal rat TG neurons; however, the intracellular signaling pathway following B 1 receptor activation remains to be elucidated. To investigate the mechanism by which B 1 receptor activation leads to intracellular Ca 2+ mobilization, we measured the intracellular free Ca 2+ concentration ([Ca 2+ ] i ) in primary-cultured TG neurons. The application of Lys-[Des-Arg 9 ]BK (B 1 receptor agonist) increased the [Ca 2+ ] i in these TG neurons even in the absence of extracellular Ca 2+ . Pretreatment with inhibitors of ryanodine receptors or sarco/endoplasmic reticulum Ca 2+ -ATPase suppressed the increase in Lys-[Des-Arg 9 ]BK-induced [Ca 2+ ] i . The Lys-[Des-Arg 9 ]BK-induced [Ca 2+ ] i increase was unaffected by phospholipase-C inhibitor. B 1 receptor activation-induced [Ca 2+ ] i increase was suppressed by phosphodiesterase inhibitor and enhanced by adenylyl cyclase inhibitor. These results suggest that B 1 receptor activation suppresses intracellular cAMP production via adenylyl cyclase inhibition and mobilizes intracellular Ca 2+ via ryanodine receptors that access intracellular Ca 2+ stores.

Opioid analgesics are widely used for the treatment of moderate to severe pain. The analgesic effects of opioids are well known to vary among individuals. The present study focused on the genetic factors that are associated with interindividual differences in pain and opioid sensitivity. We conducted a multistage genome-wide association study in subjects who were scheduled to undergo mandibular sagittal split ramus osteotomy and were not medicated until they received fentanyl for the induction of anesthesia. We preoperatively conducted the cold pressor-induced pain test before and after fentanyl administration. The rs13093031 and rs12633508 single-nucleotide polymorphisms (SNPs) near the LOC728432 gene region and rs6961071 SNP in the tcag7.1213 gene region were significantly associated with the analgesic effect of fentanyl, based on differences in pain perception latency before and after fentanyl administration. The associations of these three SNPs that were identified in our exploratory study have not been previously reported. The two polymorphic loci (rs13093031 and rs12633508) were shown to be in strong linkage disequilibrium. Subjects with the G/G genotype of the rs13093031 and rs6961071 SNPs presented lower fentanyl-induced analgesia. Our findings provide a basis for investigating genetics-based analgesic sensitivity and personalized pain control., (Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)